The incidence of melanoma has risen dramatically in recent years, but no therapy has improved overall survival for the majority of patients with unresectable metastatic disease. The University of Pittsburgh Cancer Institute (UPCI) Melanoma and Skin Cancer Program (MSCP) will continue to conduct a Specialized Program of Research Excellence (SPORE) to improve our understanding of molecular and immunologic mechanisms of cancer progression and to validate prognostic and predictive biomarkers for personalized treatment of advanced melanoma and cutaneous T cell lymphoma (CTCL). Of our 4 Projects, 1 is continued from the prior funding period, and 3 new projects have been derived from developmental research conducted in the last period; 1 of the prior SPORE projects will be continued with independent ROI funding. Our highly integrated approach leverages complementary expertise in melanoma, oncology, dermatology, immunology, biostatistics, bioinformatics, machine learning, genomics, proteomics, and biomarker discovery to test hypotheses central to the improvement of therapeutic outcome in skin cancers. Regardless of clinical outcomes, these Projects will also generate urgently needed mechanistic data to inform development of new therapeutic strategies and pathways through which to monitor relapse and progression. Our 4 Projects will evaluate: (1) the prognostic and predictive value of the pro-inflammatory response and markers of immune suppression in relation to ipilimumab and interferon (IFN) adjuvant therapy (leveraging an Eastern Cooperative Oncology Group-led adjuvant trial); (2) an engineered, 3-antigen dendritic cell vaccine and IFN boost in patients with metastatic melanoma; (3) the safety and efficacy of vemurafenib modulation of immunotherapy with IFN2b in patients with metastatic melanoma; and (4) an entirely new personalized microneedle vaccination technology in patients with melanoma and CTCL. The Administrative Core (A) coordinates the clinical research and provides scientific and fiscal oversight of the entire SPORE. The Biospecimen Core (B) is housed in the UPCI Immunologic Monitoring and Cellular Products Laboratory, where all tissue banking, biospecimen processing, and immune assays are conducted. The Biostatistics Core (C) and Informatics Core (D) support all projects with data analysis and management, respectively. We will continue to solicit, review, and fund applications for the career development and developmental research programs, which in the prior funding period led to the design of a new full project in this application (Project 3) and the promotion of career development recipients to co-investigators and a project leader.